Genetic Variant HMGB1:c.-404C>G (chr13-30464084-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000399489.5(HMGB1):c.-404C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 985,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

HMGB1
ENST00000399489.5 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.629

Publications

2 publications found

Variant links:

Genes affected

HMGB1 (HGNC:4983): (high mobility group box 1) This gene encodes a protein that belongs to the High Mobility Group-box superfamily. The encoded non-histone, nuclear DNA-binding protein regulates transcription, and is involved in organization of DNA. This protein plays a role in several cellular processes, including inflammation, cell differentiation and tumor cell migration. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Sep 2015]

HMGB1 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P

HMGB1 links:

ENSG00000285840 (HGNC:):

ENSG00000285840 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BS2

High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000399489.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HMGB1	NM_002128.7	MANE Select	c.-14-390C>G	intron	N/A	NP_002119.1
HMGB1	NM_001313892.2		c.-15+77C>G	intron	N/A	NP_001300821.1
HMGB1	NM_001313893.1		c.-14-390C>G	intron	N/A	NP_001300822.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HMGB1	ENST00000399489.5	TSL:1	c.-404C>G	5_prime_UTR	Exon 1 of 5	ENSP00000382412.1
HMGB1	ENST00000341423.10	TSL:1 MANE Select	c.-14-390C>G	intron	N/A	ENSP00000345347.5
HMGB1	ENST00000468384.1	TSL:1	n.120-390C>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000744

AC:

AN:

833110

Hom.:

Cov.:

AF XY:

0.0000883

AC XY:

AN XY:

385128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15742

American (AMR)

AF:

0.00

AC:

AN:

1114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5222

East Asian (EAS)

AF:

0.00

AC:

AN:

3676

South Asian (SAS)

AF:

0.00

AC:

AN:

16810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1620

European-Non Finnish (NFE)

AF:

0.0000775

AC:

AN:

761298

Other (OTH)

AF:

0.000110

AC:

AN:

27318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151972

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41338

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.2

(source)

DANN

Benign

0.77

PhyloP100

-0.63

PromoterAI

0.030

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over